Ring opening of aziridines with tetranitromethane in the presence of triethylamine. Efficient synthesis of β-tosylamino nitrates

Article abstract of DOI:10.1016/j.tetlet.2010.02.106

A convenient method for the preparation of β-tosylamino nitrates based on the ring-opening reaction of aziridines by tetranitromethane in the presence of triethylamine is described. A series of substituted β-amino nitrates is obtained in high yields under

Full text of DOI:10.1016/j.tetlet.2010.02.106

Tetrahedron Letters 51 (2010) 2254–2257
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ring opening of aziridines with tetranitromethane in the presence of
triethylamine. Efficient synthesis of b-tosylamino nitrates
Yuliya A. Volkova a, Elena B. Averina a,b, , Tamara S. Kuznetsova a,b, Nikolai S. Zefirov a,b
*
a Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119992, Russia
b IPhaC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region 142432, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method for the preparation of b-tosylamino nitrates based on the ring-opening reaction of
aziridines by tetranitromethane in the presence of triethylamine is described. A series of substituted b-
amino nitrates is obtained in high yields under mild conditions.
Received 2 November 2009
Revised 5 February 2010
Accepted 19 February 2010
Available online 23 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetranitromethane
Aziridines
b-Tosylamino nitrates
Organic nitrates are known to be nitric oxide (NO) releasing and
several examples have been used as drugs in clinical practice for
over a century.1 In the last 20 years intense efforts were made by
chemists towards new chemical entities, combining well-known
drugs with an NO-donating moiety, and obtaining products which
have found widespread applications in cardiovascular pharmacol-
ogy, immunology and neurobiology.2 Aminoalkyl nitrates, includ-
ing b-amino nitrates, were utilized as nitrate tethers to modify
known drug molecules.3 Also, the combination of a nitrooxy group
with an alkylamino fragment was used for the design of many
explosives.4,5 Therefore, the development of new and efficient ap-
proaches to amino nitrates and their derivatives has attracted sig-
nificant attention.
ides to give b-hydroxy nitrates.11 In continuation of our investiga-
tions on the reactivity of TNM–Et3N towards three-membered
heterocycles we studied the reactions of substituted aziridines,
N-tosylaziridines 1a–h, with TNM in the presence of triethylamine.
The starting N-tosylaziridines 1a–h were prepared via a known
procedure.12 At first we carried out a brief survey to optimize the
aziridine opening conditions for model heterocycle 1a. A screen
of solvents and reaction temperatures indicated that stirring the
reaction mixture in dioxane at 20 °C for three days (procedure
A)13 led to a clean reaction and a good isolated yield (65%) of 2a
(Table 1, entry 1). The use of microwave irradiation (procedure
B)13 was also demonstrated; the product 2a was obtained in 71%
yield in 2 h (Table 1, entry 2).
The preparation of amino nitrates is generally accomplished by
two methods: esterification of an appropriate amino alcohol3b,6
and reaction of a suitable amino alkyl halide with silver nitra-
te.3a,6a,7 However, these methods are unsuitable for large-scale
application owing to some limitations: they require strong acidic
conditions or large amounts of expensive reagents. Other methods
were used in a few instances. Recently, a few improved methods
for the synthesis of b-amino nitrates based on the ring-opening
reactions of aziridines with nitric oxide8 or bismuth9 and zirconyl10
nitrates as the source of nitrate ions were published.
The optimized reaction conditions (TNM–Et3N, dioxane, 20 °C or
microwave-assisted reaction) were successfully applied to a variety
of alkyl and aryl substituted aziridines 1a–h to provide b-nitrooxy
sulfonamides 2a–d or 3c–h in high yields.13 The results obtained
are summarized in Table 1. Symmetrical aziridines 1a,b (Table 1, en-
tries 1–3) afforded b-tosylamino nitrates 2a,b as single diastereo-
mers. It is known that fused bicyclic aziridine ring opening
proceeds via attack of the nucleophile on the three-membered ring
to give the product with trans configuration.14 The structure of 2a
was identified by X-ray crystallography (Fig. 1, CCDC-738539) and
shows that the product adopts a trans-diequatorial conformation.
The reactions of alkyl-substituted unsymmetrical aziridines 1c
and 1d with TNM–Et3N led to a mixture of two regioisomers 2c/
3c and 2d/3d in a 65:35 ratio in each case (Table 1, entries 4–6).
In both products the primary nitrates 2c and 2d prevailed over
the secondary nitrates 3c and 3d. The ring opening of aziridines
1e–h occurred with excellent regioselectivity. 1-Azaspiro[2.3]hex-
In this Letter we report a new and simple synthesis of b-tosyla-
mino nitrates via N-tosylaziridine opening with tetranitromethane
(TNM) in the presence of triethylamine. Previously, we found that
TNM–Et3N could be utilized for the efficient ring opening of epox-
* Corresponding author. Tel./fax: +7 495 9393969.
E-mail address: elaver@org.chem.msu.ru (E.B. Averina).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.106

Y. A. Volkova et al. / Tetrahedron Letters 51 (2010) 2254–2257
2255
Table 1
Reactions of N-tosylaziridines with tetranitromethane in the presence of triethylamine
TsHN
R1
ONO2
R2
O2NO
R1
NHTs
R2
Ts
N
Et3N
+
C(NO2)4
+
1,4-dioxane
R1
R2
1a-h
2a-d
b-Tosylamino nitrate 2, 3
3c,d,e-h
Entry
1
Aziridine 1
Conditions13
A
Time
3 d
Yield 2, 3 (%)
Ts
N
TsHN
ONO2
65
2
B
2 h
71
2a
1a
Ts
N
TsHN
ONO2
3
A
14 d
52
2b
1b
Ts
N
C4H9
C4H9
NHTs
ONO2
79a
ONO2
4
A
14 d
NHTs
C4H9
2c
3c
1c
2c/3c = 65/35
65a
61
Ts
N
C6H13
5
6
A
B
14 d
2 h
C6H13
NHTs
ONO2
ONO2
C6H13
NHTs
2d
3d
1d
2d/3d = 65/35
TsN
NHTs
3e
7
8
A
A
14 d
50
68
1e
ONO2
ONO2
TsN
TsN
5 d
1f
NHTs
3f
ONO2
9
A
B
14 d
2 h
67
63
10
NHTs
F
F
1g
1h
3g
ONO2
TsN
11
A
14 d
62
NHTs
Cl
Cl
3h
a
The ratio of regioisomers was determined by 1H NMR spectroscopy. Combined yield of both isomers.

2256
Y. A. Volkova et al. / Tetrahedron Letters 51 (2010) 2254–2257
[Et3NNO2]+ + C(NO2)3
C(NO2)4 + Et3N
-
C(NO2)2
C(NO2)2
NTs
1,4-dioxane
Ts
N
NHTs
1,4-dioxane
-
C(NO2)3
O-alkylation
N
N
O
-[C(NO2)2=N OH]
O
O
O
R1
R1
R1
R2
R2
R2
1
4
NHTs
TsHN
R1
ONO2
R2
[Et3NNO2]+
-Et3N
O
R1
R2
2
Scheme 1.
In summary we have developed a preparative and efficient syn-
thesis of b-tosylamino nitrates which are of potential synthetic
andpharmacological interest. Highregioselectivity, good yieldsof fi-
nalproducts, thesimplicityof procedure andtheready availabilityof
the startingreagents are the main advantages of this method making
it an interesting alternative to other b-tosylamino nitrate syntheses.
Caution: Although we did not experience any problems in han-
dling these compounds, full safety precautions should be taken due
to their potentially explosive nature.
Acknowledgements
We thank the Division of Chemistry and Materials Science RAS
(Program N 4), the President’s grant ‘Support of Leading Scientific
School’ N 5538.2008.3 (academician N.S. Zefirov), and the Russian
Foundation for Basic Research (Projects 07-03-00685-a, 10-03-
00820-a) for financial support of this work.
References and notes
Figure 1. X-ray crystal structure of compound 2a (SHELXTL PLUS).
1. Murrel, W. Lancet 1879, 113, 113–115.
2. (a) Kervin, J. F.; Lancaster, J. R.; Feldman, P. L. J. Med. Chem. 1995, 38, 4343–
4362; (b) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J.
Chem. Rev. 2002, 102, 1091–1134; (c) Thatcher, G. R. J.; Nicolescu, A. C.;
Bennett, B. M.; Toader, V. Free Rad. Biol. Med. 2004, 37, 1122–1143; (d) Bolla,
M.; Almirante, M.; Benedini, F. Curr. Top. Med. Chem. 2005, 5, 707–720; (e)
Hulsman, N.; Medema, J. P.; Bos, S.; Jongejan, A.; Leurs, R.; Smit, M. J.; Esch, I. J.;
Richel, D.; Wijtmans, M. J. Med. Chem. 2007, 50, 2424–2431; (f) Serkov, I. V.;
Bezuglov, V. V. Uspekhi Khim. 2009, 78, 442–466. Russ. Chem. Rev. 2009, 78,
407–429.
3. (a) Benedini, F.; Bertolini, G.; Cereda, R.; Dona, G.; Gromo, G.; Levi, S.; Mizrahi,
J.; Sala, A. J. Med. Chem. 1995, 38, 130–136; (b) Wey, S.-J.; Augustyniak, M. E.;
Cochran, E. D.; Ellis, J. L.; Fang, X.; Garvey, D. S.; Janero, D. R.; Letts, L. G.;
Martino, A. M.; Melim, T. L.; Murty, M. G.; Richardson, S. K.; Schroeder, J. D.;
Selig, W. M.; Trocha, A. M.; Wexler, R. S.; Young, D. V.; Zemtseva, I. S.; Zifcak, B.
M. J. Med. Chem. 2007, 50, 6367–6382; (c) Fang, L.; Appenroth, D.; Decker, M.;
Kiehntopf, M.; Roegler, C.; Deufel, T.; Fleck, C.; Peng, S.; Zhang, Y.; Lehmann, J. J.
Med. Chem. 2008, 51, 713–716.
ane tosylamide 1e and 2-aryl aziridines 1f–h afforded only the
products 3e–h as a result of ring cleavage at the more substituted
3-position (Table 1, entries 7–11), in contrast to monoalkyl-substi-
tuted aziridines 1c,d. The high regioselectivity observed in the
reactions of aziridines 1e–h with TNM–Et3N may be explained by
electronic factors. There is preference for nucleophilic attack at
the carbon atom which can better accommodate a positive charge
in the transition state.15 The structures of all the synthesized ni-
trates were unequivocally established by 1H and 13C NMR spectros-
copy and elemental analysis.
The mechanism of this reaction requires further investigation.
According to the literature, nucleophilic opening of N-tosyl-substi-
tuted aziridines15 and oxiranes11 can proceed via the pathway pre-
sented in Scheme 1. We assume that the key step of the reaction is
O-alkylation of aziridines 1 by the trinitromethyl anion to give
unstable nitronates 4 which are transformed into b-tosylamino ni-
trates 2 after solvolysis and nitration. Presumably, the source of the
proton in the final tosylamino nitrates is 1,4-dioxane.16 It is neces-
sary to employ TNM combined with triethylamine to produce the
nucleophilic species (O2N)3CÀ that reacts with the aziridines.
4. (a) Agrawal, J. P.; Hodgson, R. D. In Organic Chemistry of Explosives; Wiley:
Chichester, 2007. pp 226–227; (b) Meyer, R.; Köhler, J.; Homburg, A. Explosives;
´
Wiley: Weinheim, 2007; (c) Urbanski, T. In Chemistry and Technology of
Explosives; Pergamon Press: Oxford, 1965; Vol. 2; (d) Urban´ ski, T. In Chemistry
and Technology of Explosives; Pergamon Press: Oxford, 1984; Vol. 4.
5. Golding, P.; Millar, R. W.; Paul, N. C.; Richards, D. H. Tetrahedron 1993, 49,
7063–7076.
6. (a) Boschan, R.; Merrow, R. T.; van Dolah, R. W. Chem. Rev. 1955, 55, 485–510;
(b) Hiroyuki N.; Takashi, M.; Sakae, T.; Isao, M.; Tatsuo, K.; Toshichika, O.;

Y. A. Volkova et al. / Tetrahedron Letters 51 (2010) 2254–2257
2257
Shigeru, S.; Minoru, S. Patent DE 2714713, 1977; Chem. Abstr. 1978, 88, 22652h;
(c) Romanova, L. B.; Ivanova, M. E.; Nesterenko, D. A.; Eremenko, L. T. Izv. RAN
Ser. Khim. 1994, 1271–1272. Russ. Chem. Bull. 1994, 43, 1207–1208.
7. (a) López, G. V.; Batthyany, C.; Blanco, F.; Botti, H.; Trostchansky, A.; Migliaro,
E.; Radi, R.; González, M.; Cerecetto, H.; Rubbo, H. Bioorg. Med. Chem. 2005, 13,
5787–5796; (b) López, G. V.; Blanko, F.; Hernandez, P.; Ferreira, A.; Piro, O. E.;
Batthyány, C.; González, M.; Rubbo, H.; Cerecetto, H. Bioorg. Med. Chem. 2007,
15, 6262–6272; (c) Fotopoulou, T.; Iliodromitis, E. K.; Koufaki, M.; Tsotinis, A.;
Zoga, A.; Gizas, V.; Pyriochou, A.; Papapetropoulos, A.; Andreadou, I.;
Kremastinos, D. Th. Bioorg. Med. Chem. 2008, 16, 4523–4531.
8. Liu, Z.-K.; Fan, Y.; Li, R.; Zhou, B.; Wu, L.-M. Tetrahedron Lett. 2005, 46, 1023–
1025.
9. Das, B.; Krishnaiah, M.; Venkateswarlu, K. Tetrahedron Lett. 2006, 47, 6027–
6029.
10. Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Reddy, V. S. Helv. Chim. Acta 2007,
90, 110–113.
(s, 3H, CH3), 3.47 (d, 3J = 6.7 Hz, 2H, CH2NH), 5.14 (br t, 3J = 6.7 Hz, 1H, NH), 7.33
(d, 3J = 8.2 Hz, 2H, 2 Â CH), 7.76 (d, 3J = 8.2 Hz, 2H, 2 Â CH); 13C NMR (100 MHz,
CDCl3): d 13.3 (CH2), 21.5 (CH3), 30.3 (2 Â CH2), 45.5 (CH2NH), 86.8 (CONO2),
127.0 (2 Â CH, Ph), 129.9 (2 Â CH, Ph), 136.8, 143.8 (C); IR (KBr):
mmax 3297 (w,
br), 1627 (s), 1427 (s), 1307 (s) cmÀ1; Anal. Calcd for C12H16N2O5S: C, 47.99; H,
5.37; N, 9.33. Found: C, 47.55; H, 5.14; N, 9.31.
1-(2-Fluorophenyl)-2-(4-methylphenylsulfonamido)ethyl nitrate (3g). Yellow oil;
Rf 0.53 (hexane–ethyl acetate, 4:1); 1H NMR (400 MHz, CDCl3): d 2.44 (s, 3H,
CH3), 3.35–3.54 (m, 2H, CH2NH), 5.16–5.23 (m, 1H, NH), 6.10 (dd, 3J = 4.1,
8.6 Hz, 1H, CHONO2), 7.06–7.17 (m, 2H), 7.27–7.37 (m, 2H), 7.31 (d, 3J = 8.3 Hz,
2H, 2 Â CH), 7.77 (d, 3J = 8.3 Hz, 2H, 2 Â CH); 13C NMR (100 MHz, CDCl3): d 21.6
(CH3), 44.8 (CH2NH), 77.7 (CHONO2), 116.1 (d, J = 21.0 Hz, CH), 122.1 (d,
J = 13.3 Hz, C), 124.8 (CH), 127.0 (2 Â CH), 127.6 (CH), 130.0 (2 Â CH), 131.3
(CH), 136.8 (C), 144.0 (C), 160.1 (d, J = 249.6 Hz, C); IR (KBr): mmax 3280 (w, br),
1643 (s), 1455 (s), 1330 (s) cmÀ1; Anal. Calcd for C15H15FN2O5S: C, 50.84; H,
4.27; N, 7.91. Found: C, 50.65; H, 4.07; N, 7.77.
11. Volkova, Y. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.; Kuznetsova, T. S.;
Zefirov, N. S. Tetrahedron Lett. 2008, 49, 3935–3938.
12. Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1998, 54,
13485–13494.
13. General procedure A: Triethylamine (0.14 ml, 1 mmol) was added gradually at
5 °C to a solution of TNM (0.22 ml, 2 mmol) in 1,4-dioxane (2 ml). The mixture
was stirred for 5 min with cooling, after which the corresponding aziridine
(1 mmol) was added. The resulting mixture was stirred at room temperature
for the specified time according to Table 1. TLC and NMR spectra were used to
monitor the progress of the reactions. On completion, the solvent was
evaporated and the product was isolated by column chromatography
(hexane–ethyl acetate, 4:1).
1-(2-Chlorophenyl)-2-(4-methylphenylsulfonamido)ethyl nitrate (3h). Yellow oil;
Rf 0.49 (hexane–ethyl acetate, 4:1); 1H NMR (400 MHz, CDCl3): d 2.45 (s, 3H,
CH3), 3.28–3.43 (m, 2H, CH2NH), 5.27 (br dd, 3J = 5.7, 7.5 Hz, 1H, NH), 5.80 (dd,
3J = 4.5, 8.5 Hz, 1H, CHONO2), 7.15–7.34 (m, 6H), 7.73 (d, 3J = 8.1 Hz, 2H,
2 Â CH); 13C NMR (100 MHz, CDCl3):
d 21.6 (CH3), 45.8 (CH2NH), 82.6
(CHONO2), 124.7, 126.6 (CH, Ph), 127.0 (2 Â CH, Ph), 129.9 (CH, Ph), 130.0
(2 Â CH, Ph), 130.5 (CH), 135.1 (C), 136.6 (C), 136.7 (C), 144.2 (C); IR (KBr): mmax
3280 (w, br), 1643 (s), 1477 (s), 1330 (s) cmÀ1; Anal. Calcd for C15H15ClN2O5S:
C, 48.59; H, 4.08; N, 7.55. Found: C, 48.75; H, 4.09; N, 7.39.
14. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619; (b) McCoull, W.;
Davis, F. A. Synthesis 2000, 1347–1365; (d) Hu, X. E. Tetrahedron 2004, 60,
2701–2743.
General procedure B: The procedure was carried out as described above using a
CEM-discover monomode system. The reaction mixture was placed into a
microwave vessel (10 ml) containing a Teflon-coated magnetic stirrer bar. The
sample was irradiated for 2 h. For safety, the maximum power was set to 10 W
and the maximum temperature was set to 50 °C. On completion, the solvent
was evaporated and the product was isolated by column chromatography
(hexane–ethyl acetate, 4:1).
15. (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258; (b) D’hooghe, M.; Kerkaert,
I.; Rottiers, M.; De Kimpe, N. Tetrahedron 2004, 60, 3637–3641; (c) D’hooghe,
M.; Rottiers, M.; Kerkaert, I.; De Kimpe, N. Tetrahedron 2005, 61, 8746–8751;
(d) D’hooghe, M.; De Kimpe, N. Synlett 2004, 271–274.
16. In the NMR spectra of the reaction mixtures of the aziridines with TNM–Et3N,
we observed signals which presumably can be attributed to mononitro
substituted 1,4-dioxane. An analogous process was identified in our previous
work using THF.17
Spectral and analytical data of representative products:
1-[(4-Methylphenylsulfonamido)methyl]cyclobutyl nitrate (3e). Pale yellow solid;
mp = 87–89 °C; Rf 0.40 (hexane–ethyl acetate, 4:1); 1H NMR (400 MHz, CDCl3):
d 1.69–1.84 (m, 1H, CH2), 1.93–2.04 (m, 1H, CH2), 2.25–2.37 (m, 4H, CH2), 2.45
17. Volkova, Yu. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.; Kuznetsova, T. S.;
Zefirov, N. S. Izv. AN, Ser. Khim. 2008, 1999–2000. Russ. Chem. Bull. 2008, 57,
2034–2035.